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Biomedical subjects

G E Adams

Publications and source records attributed to G E Adams.

At least 109 records · Page 6Linked to original sources
PubMed1983

Abnormal radiosensitizing and cytotoxic properties of ortho-substituted nitroimidazoles.

Various 5-substituted 4-nitroimidazoles have been shown to be much more efficient radiosensitizers and much more toxic than would have been predicted from their electron affinities, as measured by values of one-electron reduction potential, E17. Using Chinese hamster V79 cells in vitro, a comparison has been made with some isomeric 4-substituted 5-nitroimidazoles. These compounds have E17 values some 64mV greater than the 4-nitroimidazoles, yet show much lower sensitizing efficiency and also lower toxicity. Neither series of compounds shows the greater toxicity towards hypoxic cells usually associated with nitroaromatic and nitroheterocyclic compounds. The second-order rate constants, k2, for reaction of these isomeric nitroimidazoles with glutathione and dithiothreitol were determined. Within each series the value of k2 increased with increasing electron affinity, however, the 4-nitroimidazoles were always more reactive than their corresponding 5-nitro isomers. The sensitizing and toxic properties of these compounds may involve depletion of intracellular thiols; this possibility is discussed.

Animals↗
PubMed1983

Radiosensitization in vivo: a study with an homologous series of 2-nitroimidazoles.

An homologous series of 1-(omega-morpholino)alkyl-2-nitroimidazoles, previously reported to be more efficient hypoxic cell radiosensitizers than misonidazole (MIS) in vitro, were evaluated in vivo using the murine Lewis Lung carcinoma. When given i.p. the compounds were 3-20 times more acutely toxic (LD50/2d) than MIS and this toxicity increased with both the number of methylene groups (n) in the side chain and the lipophilicity of the compounds. The compounds sensitized the tumour to single doses of X-rays. On the basis of equimolar administered dose, the most effective compounds, n = 2, 4 and 5, were as efficient as MIS. However, on the basis of the measured concentration of drug in the tumour at the optimum time of irradiation the compounds with n = 4 and n = 5 were less efficient than expected from previously published data in vitro. This is attributed to the basicity of the morpholino nitrogen in these compounds such that at physiological pH the compounds are primarily in an ionized form and hence poorly able to penetrate hypoxic cells.

Animals↗
PubMed1982

Enhancing effect of pre-treatment of cells with misonidazole in hypoxia on their response to melphalan in air.

Pre-treatment of hypoxic cells with misonidazole (MISO) can render these cells more sensitive to a subsequent treatment with melphalan. Results in this paper show that this enhancement (or chemopotentiation) depends on the contact time and concentration of MISO, on the melphalan concentration and also on the cultural history of the cells. Damage due to hypoxic pre-incubation in MISO can be repaired if cells are subsequently aerated at 37 degrees C. In contrast, for cells washed free of MISO and then held under N2 at 37 degrees C, repair is much slower. No repair occurs when cells are held in air at 0 degrees C. The kinetics and extent of repair were dependent on the cells prior culture. Thus for exponential cells repair was complete after approximately 4 h, whereas for plateau-phase cells and cells with prior chronic hypoxia, repair was only partially complete after this time. Dithiothreitol was shown to protect partially against the enhancement of melphalan toxicity. Increased cell killing is also obtained if cells are given high concentrations of MISO (50 mM) in air during exposure to melphalan.

Animals↗
PubMed1982

Potentiation of melphalan activity against a murine tumour by nitroimidazole compounds.

The activity against murine anaplastic MT tumours of the chemotherapeutic agent melphalan, either alone or in combination with one of 6 nitroimidazole compounds, was assayed using an in vivo-in vitro tumour excision assay. The melphalan alone proved cytotoxic to the tumour, whereas relatively little cytotoxicity was produced by any of the nitroimidazoles alone. When the nitroimidazole were given in combination with melphalan, dose-modifying potentiation of its cytotoxicity was observed. Maximum potentiation occurred when the nitroimidazoles were given 0--30 min before the melphalan, although some potentiation was still evident when they were given up to 2 h before or after. There was no threshold in nitroimidazole dose required to produce this potentiation, the degree of potentiation increasing with dose, albeit at a diminishing rate, to give maximum dose-modification factors of about 3. The 6 nitroimidazole compounds in order of increasing effectiveness as potentiators of melphalan activity were: METRO, Ro 05-9963, MISO, RSU 1047, Ro 03-8800 and Ro 03-8799. This order corresponds to the increasing electron affinity of these compounds. The most effective compound here, Ro 03-8799, was about twice as effective as the most widely used nitroimidazole in such studies, MISO.

Animals↗
PubMed1982

Enhancement of the cytotoxicity of radiosensitizers by modest hyperthermia: the electron-affinity relationship.

The cytotoxicity of 3 electron-affinic radiosensitizers has been studied in Chinese hamster V-79 cells as a function of pH and modest hyperthermia. When equitoxic concentrations were used and temperature was increased from 34 to 41 degrees C metronidazole, the compound with the lowest electron affinity showed the greatest enhancement of hypoxic-cell toxicity, and nitrofurantoin, the compound with the highest electron affinity, the least. The results can be explained if the mechanisms of toxicity involves a redox reaction, since it would be expected that the least toxic compound (lowest electron affinity) would have the largest activation energy and hence the greatest temperature effect. This appears to hold for these 3 compounds. Experiments also showed that nitrofurantoin which exhibits no increase in toxicity when the temperature was increased from 37 to 41 degrees C at pH 7.4, showed an increase in toxicity for the same temperature change at the pH of 7.0 and 6.6. Under aerobic conditions only metronidazole showed significant toxicity at 41 degrees C, where the differential between aerobic and hypoxic cell toxicity was minimal, both at pH 7.4, and at the low pH values of 7.0 and 6.6. In the clinical setting there is evidence that tumour cells are at a lower pH than their surrounding normal tissues. Hypoxic-cell cytotoxicity is enhanced at low pH, and even further enhanced at low pH in combination with a temperature of 41 degrees C. However, this finding correlates conversely with electron affinity. Thus, the radiosensitizer (and trichomonicide) metronidazole is most influenced by low pH and high temperature with the nitroimidazole, misonidazole, demonstrating a smaller enhancement due to higher temperatures.

Animals↗
PubMed1982

Interaction of the cytotoxic and sensitizing effects of electron-affinic drugs and hyperthermia.

Both published and new data on the interaction of electron-affinic drugs with hyperthermia with and without irradiation are reviewed for systems both in vitro and in vivo. Modest (sublethal) hyperthermia (41 degrees C) augments the differential hypoxic cytoxicity of some electron-affinic agents. Although hypoxic cytotoxicity increases with electron affinity, the thermal enhancement factors decrease. This finding is further evidence that hypoxic cytotoxicity and radiosensitization occur by different mechanisms. Furthermore, sublethal exposure of hypoxic cells to these agents makes them sensitive to killing by heat, which implies that because, under some circumstances, chronically hypoxic, unlike acutely hypoxic, cells can be thermally tolerant and could be important in the hyperthermic treatment of tumors.

Anaerobiosis↗
PubMed1981

Radiosensitization of hypoxic mammalian cells in vitro by some 5-substituted-4-nitroimidazoles.

The efficiencies of various 5-substituted-4-nitroimidazoles as radiation sensitizers have been determined in hypoxic Chinese hamster cells irradiated in vitro. Compared with published data on the sensitizing properties of substituted 2-nitro- and 5-nitroimidazoles, some of the 4-nitro derivatives show unusually high sensitizing efficiencies defined as the concentrations required to give an enhancement ratio of 1.6. The equilibrium one-electron reduction potentials of the compounds (E17) were measured by a pulse radiolysis technique and the results show that although sensitizing efficiencies are unexpectedly high, based on considerations of electron affinity, they still increase with increasing values of E17. Enhancement ratios were determined in two V79 cell lines for combinations of one of these compounds (a 4-nitroimidazole containing the group SO2.O.phenyl in the 5-position, NSC 38087) with various concentrations of misonidazole. The sensitization observed suggests that the two compounds may be operating by different mechanisms.

Animals↗
PubMed1980

Time effects in molecular radiation biology.

Radiation action occurs over a broad timescale which extends from the very early physical processes associated with energy absorption to the very late biological effects, such as carcinogenesis which may not become apparent until many years later. The various temporal stages of radiation action are classified and their interrelationships described. Experimental projects in cellular radiation chemistry, including pulse radiolysis, are discussed, together with some applications of the techniques in this general area. The paper also deals with some aspects of the oxygen effect in radiobiology and the mechanisms of its action. Various studies employing fast response techniques have been useful in verifying the role of fast free radical reactions in the oxygen effects and examples are given of some applications. Investigations with other hypoxic cell sensitizers, the electron affinic agents, are also briefly discussed, with an account of how studies of the timescale of radiation sensitization can be valuable in understanding mechanisms. Possible mechanisms of action of radiation sensitization by oxygen and other agents, including radical fixation and direct action processes, are considered in the light of evidence from some model systems.

Animals↗
PubMed1980

Cytotoxicity of adriamycin on aerobic and hypoxic chinese hamster V79 cells in vitro.

Mammalian cells (V79-379A) in suspension culture rendered chronically hypoxic showed greater resistance to Adriamycin than exponentially growing aerobic cells. Resistance to Adriamycin increased as a function of the time cells were held under hypoxic conditions, with maximal resistance after 6 h. Chronically hypoxic cells retained their resistance when reoxygenated, and did not return to their original sensitivity until they had been in air for 24 h. Uptake of Adriamycin was similar for chronically hypoxic and exponentially growing aerobic cells, but much more than for plateau-phase cells. These findings suggest that chronically hypoxic cells in tumours may be resistant to this drug.

Aerobiosis↗
PubMed1980

Combination studies with misonidazole and a cis-platinum complex: cytotoxicity and radiosensitization in vitro.

cis-Dichlorodiammineplatinum(II) (cis-Pt(II) can act as a radiosensitizer of hypoxic mammalian cells in vitro. Used in combination with misonidazole the level of sensitization achieved is greater than that seen with either drug alone, and it is suggested that these compounds sensitize by independent mechanisms. For cells held at 37 degrees C, cis-Pt(II) shows much greater toxicity to hypoxic cells than to aerobic cells. In combination with misonidazole, no additional cytotoxic effect is shown towards aerobic cells than that seen for cis-Pt(II) alone. However, there is additional killing of hypoxic cells when they are treated with both drugs.

Animals↗
PubMed1980

Structure-activity relationships in the development of hypoxic cell radiosensitizers. III. Effects of basic substituents in nitroimidazole sidechains.

The effects of substituting 2-nitroimidazoles with groups carrying basic functions were studied. Prototropic, redox, lipophilicity and protein-binding properties were compared with the efficiency in radiosensitizing hypoxic Chinese hamster V79-379A cells in vitro and the cytotoxicities of the compounds after chronic aerobic exposure. Seventeen compounds were (2-nitro-1-imidazolyl)alkylamines in which the effects of changes in the terminating base and of alkyl chain length were investigated. About an order of magnitude increase in sensitization efficiency could be observed in some compounds without any increase in the aerobic cytotoxicity compared to simple, uncharged 2-nitroimidazoles such as misonidazole. The behaviour of five hydrazones was similar to that of uncharged analogues. The methiodide quaternary salts of two of the (2-nitro-1-imidazolyl)alkylamines showed that quaternization considerably reduced sensitization efficiency. (Nitro-1-imidazolyl)alkylamines appear worthy of further investigation as hypoxic cell radiosensitizers in vivo.

Animals↗
PubMed1980

Toxicity of nitro compounds toward hypoxic mammalian cells in vitro: dependence on reduction potential.

Fifteen nitroaromatic and nitroheterocyclic compounds that can act as "radiosensitizers" were tested for their cytotoxicity toward hypoxic Chinese hamster V79 cells in vitro. The cytotoxicity increased markedly as the electron affinity, measured as a one-electron reduction potential, increased. Non-nitro-containing compounds of similar electron affinities (such as quinones) that also act as radiosensitizers did not exhibit this specific toxicity toward hypoxic cells. The implications of the presence of the nitro group as a prerequisite for the hypoxic cell toxicity were discussed, and the mechanism of the cytotoxicity was compared with that of hypoxic cell radiosensitization.

Animals↗